Restenosis following vascular interventions results from neointimal hyperplasia and/or geometric remodeling. However, the early response following vascular injury is not well understood. Up-regulation of adhesion molecules and leukocyte recruitment and activation appear to be important events. Adenosine modulates the inflammatory response following vascular injury and many of these effects are mediated by the A2A receptor. We have demonstrated that a 7 day administration of the specific A2A receptor agonist DWH-146e decreases neointimal formation and leukocyte recruitment following carotid ligation in the mouse. However, the optimal duration of therapy is not known and an ideal drug would have a long duration of action. Accordingly, Aim 1 of this proposal is to determine the optimal therapeutic window for administration of the A2A agonist, DWH146e, to produce maximal reduction in neointimal growth after vascular injury. Aim 2 is to synthesize and evaluate a new potent, stable and long acting specific A2A agonist for maximal vascular protection. We have developed a scheme to efficiently synthesize adenosine analogs that are potent and highly selective agonists of A2A adenosine receptors. We plan to identify the metabolites that accumulate in animals by using bioassays and chemical detection methods. This work will be done by Adenosine Therapeutics, LLC. PROPOSED COMMERCIAL APPLICATIONS: We propose to synthesize, characterize and commercialize novel adenosine A2A agonists in order to reduce the neointimal response to vascular injury. Restenosis remains a significant problem after vascular interventions, occurring in 20-40 % of cases. Our exciting preliminary data suggests a strategy to significantly limit this process. We anticipate that these studies will provide important insights into the role of inflammation after vascular injury. This work may have considerable clinical impact with respect to enhancing the effectiveness of angioplasty, reducing morbidity and limiting the overall cost of atherosclerotic vascular disease.